Unlike simple single-gene genetic disease, alcohol-related behaviors are influenced by many genes and by environmental factors as well. Such polygenic, multifactorial pheno-types represent a challenge for the application of the new molecular genetic techniques. The goal of the proposed three and one-half year project is to identify associations between genetic markers and alcohol-related traits even when such associations account for only a small amount of variance. Research in the field of plant genetics indicates that most genetic markers are likely to show some associations with complex characteristics. Two components of the project will proceed simultaneously: Testing unique inbred strains of mice [BxD recombinant inbred (RI) strains] on an extensive battery of alcohol-related traits and characterizing these strains in terms of new genetic markers, restriction fragment length polymorphisms (RFLPs). The battery assessing many components of alcohol sensitivity preference, acceptance, activation, acute tolerance, metabolic rate, hypothermia, and dependence will be administered to 16 mice for each of the 26 RI strains available from the C57BL/6 and DBA/2 parental strains and to the 52 backcrosses of the RI strains to their progenitor inbred strains. In addition to providing a powerful tool for screening alcohol-related phenotypes for major gene effects and for determining linkage of any such loci of major effect with genetic markers, the RI strains are particularly valuable for the proposed research because they have already been categorized in terms of over 150 genetic markers, and new markers, especially RFLP markers, are appearing at an accelerating pace. Between already described markers for the 26 RI strains and the battery of alcohol related behaviors to be assessed in our proposed research, associations can be detected that account for about 10% of the variance. The addition of the backcrosses makes it possible to detect associations that account for as little as 3% of the variance and to explore dominance effects. Testing the RI lines and backcrosses for many alcohol-related measures that have no or low intercorrelations greatly increases the chances of finding associations with genetic markers. Multivariate analysis of many genetic markers permits the discovery of combinations of genetic markers that are associated with alcohol-related phenotypes. The synergism created by this attempt to merge quantitative genetics and molecular genetics has great potential to advance our understanding of multifactorial alcohol-related phenomena.